4TVK
TORPEDO CALIFORNICA ACETYLCHOLINESTERASE IN COMPLEX WITH A CHLOROTACRINE-JUGLONE HYBRID INHIBITOR
Summary for 4TVK
| Entry DOI | 10.2210/pdb4tvk/pdb |
| Descriptor | Acetylcholinesterase, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total) |
| Functional Keywords | multitarget drug, enzyme-inhibitor complex, tacrine, quinone, hydrolase |
| Biological source | Torpedo californica (Pacific electric ray) |
| Cellular location | Isoform H: Cell membrane; Lipid-anchor, GPI- anchor. Isoform T: Cell membrane; Peripheral membrane protein: P04058 |
| Total number of polymer chains | 1 |
| Total formula weight | 61761.94 |
| Authors | Pesaresi, A.,Samez, S.,Lamba, D. (deposition date: 2014-06-27, release date: 2014-10-08, Last modification date: 2024-11-20) |
| Primary citation | Nepovimova, E.,Uliassi, E.,Korabecny, J.,Pena-Altamira, L.E.,Samez, S.,Pesaresi, A.,Garcia, G.E.,Bartolini, M.,Andrisano, V.,Bergamini, C.,Fato, R.,Lamba, D.,Roberti, M.,Kuca, K.,Monti, B.,Bolognesi, M.L. Multitarget Drug Design Strategy: Quinone-Tacrine Hybrids Designed To Block Amyloid-beta Aggregation and To Exert Anticholinesterase and Antioxidant Effects. J.Med.Chem., 57:8576-8589, 2014 Cited by PubMed Abstract: We report the identification of multitarget anti-Alzheimer compounds designed by combining a naphthoquinone function and a tacrine fragment. In vitro, 15 compounds displayed excellent acetylcholinesterase (AChE) inhibitory potencies and interesting capabilities to block amyloid-β (Aβ) aggregation. The X-ray analysis of one of those compounds in complex with AChE allowed rationalizing the outstanding activity data (IC50 = 0.72 nM). Two of the compounds showed negligible toxicity in immortalized mouse cortical neurons Neuro2A and primary rat cerebellar granule neurons. However, only one of them was less hepatotoxic than tacrine in HepG2 cells. In T67 cells, both compounds showed antioxidant activity, following NQO1 induction. Furthermore, in Neuro2A, they were able to completely revert the decrease in viability induced by Aβ. Importantly, they crossed the blood-brain barrier, as demonstrated in ex vivo experiments with rats. When ex vivo results were combined with in vitro studies, these two compounds emerged to be promising multitarget lead candidates worthy of further pursuit. PubMed: 25259726DOI: 10.1021/jm5010804 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.3 Å) |
Structure validation
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